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COX6A2 variants cause a muscleā€specific cytochrome c oxidase deficiency

Authors :
Leentje Van Lommel
Ikuya Nonaka
Tsutomu Takahashi
Katsunori Fujii
Masakazu Mimaki
Ichizo Nishino
Michio Inoue
Hirofumi Komaki
Shinichiro Hayashi
Takuya Yoshizawa
Yu-ichi Goto
Satoru Noguchi
Shumpei Uchino
Yukinori Okada
Aritoshi Iida
Eri Takeshita
Frans Schuit
Source :
Annals of Neurology. 86:193-202
Publication Year :
2019
Publisher :
Wiley, 2019.

Abstract

OBJECTIVE Cytochrome c oxidase (COX) deficiency is a major mitochondrial respiratory chain defect that has vast genetic and phenotypic heterogeneity. This study aims to identify novel causative genes of COX deficiency with only striated muscle-specific symptoms. METHODS Whole exome sequencing was performed in 2 unrelated individuals who were diagnosed with congenital myopathy and presented COX deficiency in muscle pathology. We assessed the COX6A2 variants using measurements of enzymatic activities and assembly of mitochondrial respiratory chain complexes in the samples from the patients and knockout mice. RESULTS Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness. One patient had cardiomyopathy. Neither patient exhibited involvement from other organs. Whole exome sequencing identified biallelic missense variants in COX6A2, which is expressed only in the skeletal muscle and heart. The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg). We found specific reductions in complex IV activities in the skeletal muscle of both individuals. Assembly of complex IV and its supercomplex formation were impaired in the muscle. INTERPRETATION This study indicates that biallelic variants in COX6A2 cause a striated muscle-specific form of COX deficiency. ANN NEUROL 2019;86:193-202.

Details

ISSN :
15318249 and 03645134
Volume :
86
Database :
OpenAIRE
Journal :
Annals of Neurology
Accession number :
edsair.doi.dedup.....a73f05cddbef1ee2471e55140ff531e2